Design and synthesis of non proteinogenic amino acids represent a central issue for chemists working in the area of medicinal chemistry and among them, unsaturated beta-amino acids have attracted high interest as valuable intermediates in the synthesis of dehydropeptides, allowing the preparation of conformationally constrained sequences with improved biological activity and selectivity. In particular, we are interested to the synthesis of receptor-selective peptides and peptidomimetics, mimicking the RGD motif, present in a wide number of extracellular matrix proteins. These ligands bind to Alpha-v-beta-3 and Alpha- 5-beta-1 integrins, a large family of heterodimeric transmembrane glycoproteins, involved in the pathogenesis of several diseases, such as atheroschlerosis, osteoporosis, cancer and a variety of inflammatory disorders. In view of the application as central cores of peptidomimetics, we have developed synthetic strategies for the preparation of linear and cyclic dehydro--amino acids, using alkylidene acetoacetates and malonates as starting materials. The use of five membered heterocycles as proline analogues has been extensively explored to induce conformational restraints in peptidomimetics. We have recently developed the synthesis of 5-hydroxyisoxazolidine-4-carboxylate, and related functionalized isoxazolines, as heterocycles containing the dehydro-beta-amino carboxylate fragment. Lewis acid induced Michael addition of hydroxylamine derivatives to alkylidene acetoacetates, followed by intramolecular hemiketal formation, allowed to obtain a small library of functionalized isoxazoline-based integrin ligands. Moreover, transformation of alkylidene derivatives into the corresponding allylic carbonates furnished linear dehydro-beta-amino acids, through regio- and stereoselective allylic amination in the presence of palladium and iridium catalysts. Introduction of an allylamino moiety through the SN2’ reaction, gave also access to an intermediate containing two unsaturations, thus suggesting that RCM could be a valuable tool for the preparation of dihydropyrrole scaffold. Decoration of the dehydro-beta-amino acid cores with the proper appendages to mimic aspartate and arginine side chains, afforded structures possessing excellent receptor affinity as confirmed by cell adhesion inhibition assays.
Dehydro-beta-amino acid containing peptidomimetics as integrin receptor ligands
TOLOMELLI, ALESSANDRA;VIOLA, ANGELO;GENTILUCCI, LUCA;MOSCONI, ELISA;DE MARCO, ROSSELLA;BAIULA, MONICA;SPAMPINATO, SANTI MARIO;
2012
Abstract
Design and synthesis of non proteinogenic amino acids represent a central issue for chemists working in the area of medicinal chemistry and among them, unsaturated beta-amino acids have attracted high interest as valuable intermediates in the synthesis of dehydropeptides, allowing the preparation of conformationally constrained sequences with improved biological activity and selectivity. In particular, we are interested to the synthesis of receptor-selective peptides and peptidomimetics, mimicking the RGD motif, present in a wide number of extracellular matrix proteins. These ligands bind to Alpha-v-beta-3 and Alpha- 5-beta-1 integrins, a large family of heterodimeric transmembrane glycoproteins, involved in the pathogenesis of several diseases, such as atheroschlerosis, osteoporosis, cancer and a variety of inflammatory disorders. In view of the application as central cores of peptidomimetics, we have developed synthetic strategies for the preparation of linear and cyclic dehydro--amino acids, using alkylidene acetoacetates and malonates as starting materials. The use of five membered heterocycles as proline analogues has been extensively explored to induce conformational restraints in peptidomimetics. We have recently developed the synthesis of 5-hydroxyisoxazolidine-4-carboxylate, and related functionalized isoxazolines, as heterocycles containing the dehydro-beta-amino carboxylate fragment. Lewis acid induced Michael addition of hydroxylamine derivatives to alkylidene acetoacetates, followed by intramolecular hemiketal formation, allowed to obtain a small library of functionalized isoxazoline-based integrin ligands. Moreover, transformation of alkylidene derivatives into the corresponding allylic carbonates furnished linear dehydro-beta-amino acids, through regio- and stereoselective allylic amination in the presence of palladium and iridium catalysts. Introduction of an allylamino moiety through the SN2’ reaction, gave also access to an intermediate containing two unsaturations, thus suggesting that RCM could be a valuable tool for the preparation of dihydropyrrole scaffold. Decoration of the dehydro-beta-amino acid cores with the proper appendages to mimic aspartate and arginine side chains, afforded structures possessing excellent receptor affinity as confirmed by cell adhesion inhibition assays.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
